{
  "abstract": "Despite the success of immune checkpoint blockade in cancer therapy, overcoming the immunosuppressive tumor microenvironment remains a major barrier to durable responses. Here, we introduce cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)-targeting chimeras (cTACs), a class of synthetic molecules that harness CTLA-4-mediated trans-endocytosis (TE) for targeted protein degradation across cellular boundaries. The lead candidate, cTAC4.0, is composed of the extracellular domain of CD80 fused to an anti-programmed death-ligand 1 (PD-L1) fragment via a human immunoglobulin G4 (IgG4) heavy chain. Unlike existing protein degraders that function within cancer cells via house-keeping pathways, cTAC4.0 operates in trans between immune and tumor cells. It redirects the natural CD80-CTLA-4 internalization to capture and degrade PD-L1 from tumor cells into T cells, while simultaneously converting PD-L1-mediated suppression into CD28-driven co-stimulation, depending on the relative availability of CTLA-4 or CD28. Mechanistically, we demonstrate that cTAC4.0 promotes CTLA-4-dependent internalization and lysosomal degradation of both membrane-bound and soluble PD-L1, reduces surface PD-L1 levels on target cells, and activates T cells in a CD28-dependent manner. Functionally, cTAC4.0 enhances the cytotoxicity of both bispecific T cell engagers and T cell receptor (TCR)-engineered T cells in vitro, and when combined with these engineered T cells, it suppresses tumor growth in vivo in a glioblastoma xenograft model. By coupling immune checkpoint degradation with T cell activation in an immune synapse-enriched manner, cTACs establish a paradigm for intercellular protein degradation systems that simultaneously deplete suppressive ligands and enhance T cell function to overcome resistance in cancer immunotherapy.",
  "abstract_shown": true,
  "affiliations": [
    "11. Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, USA 12. Ellen and Ronald Caplan Cancer Center, The Wistar Institute, Philadelphia,"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "name": "P. Ren"
    },
    {
      "name": "S.-Y. Fang"
    },
    {
      "name": "S. Zhao"
    },
    {
      "name": "H. Cao"
    },
    {
      "name": "K. Tang"
    },
    {
      "name": "X. Shang"
    },
    {
      "name": "C. W. Christopher"
    },
    {
      "name": "Y. Jiao"
    },
    {
      "name": "M. Majety"
    },
    {
      "name": "A. Levchenko"
    },
    {
      "name": "D. B. Weiner"
    },
    {
      "name": "S. Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "X. Zhou"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7s2s3wqbcc3cz.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.29.755403",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.29.755403v1.full",
  "id": "7s2s3wqbcc3cz",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.29.755403v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "immunology"
    ],
    [
      "openalex",
      "2730|Cancer Immunotherapy and Biomarkers"
    ]
  ],
  "openalex": "W7216548112",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.29.755403v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-29",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/7s2s3wqbcc3cz.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:25:49Z",
      "native_id": "10.64898/2026.09.29.755403",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.29.755403v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:immunology",
      "subfield": "immunology"
    }
  ],
  "title": "Engineered CTLA-4 targeting chimeras for targeted protein degradation and immune synapse reprogramming",
  "title_text": "Engineered CTLA-4 targeting chimeras for targeted protein degradation and immune synapse reprogramming",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:49Z",
  "url": "https://research.draconitic.com/paper/7s2s3wqbcc3cz",
  "venue": "bioRxiv",
  "versions": []
}